Over 100,000 patients with alcohol use disorders develop sepsis annually. Septic patients with chronic alcohol abuse have increased mortality and severity of multiple organ dysfunction compared to septic patients without a history of alcohol abuse. We have created a murine model that replicates the increased mortality seen in alcoholic septic patients compared to patients who develop sepsis without a history of alcohol abuse. While the majority of organs are similar between alcohol-fed and water-fed septic mice, we found that both gut integrity and the immune system are severely dysregulated in alcohol-fed septic mice. Two key and complementary themes emerged in comparing alcohol-fed septic mice and water-fed septic mice: 1) abnormalities in gut integrity and the immune response are exacerbated in alcohol-fed septic mice and perhaps more importantly, 2) there are a number of mechanisms that appear to be specific to the combination of sepsis and chronic alcohol usage. Specifically, multiple abnormalities are present with the combination of chronic alcohol ingestion and sepsis that are not present with either chronic alcohol ingestion or sepsis in isolation. The proposal seeks to understand these mechanisms by examining both gut integrity (apoptosis, permeability, proliferation, and villus length) and the host immune response (primarily focusing on CD4+ T cells and NK cells). Finally, the proposal examines crosstalk between the gut and the immune system, seeking to understand how changing gut integrity alters the host response and reciprocally how altering the immune response changes gut integrity in alcohol-fed septic mice. Since septic hosts with alcohol use disorders appear to respond differently to a septic insult than those without a history of alcohol abuse, this may require a different therapeutic approach than would be needed in a typical septic host. Understanding the mechanisms underlying mortality in sepsis following chronic alcohol ingestion therefore has significant public health implications in a disease that is common, very costly, and highly lethal.